Nonsteroidal anti-inflammatory drugs (NSAIDs) and spontaneous abortion Pharmacovigilance and Special Access Branch Safety Review Version 1.0, September 2016
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Safety review: Nonsteroidal anti-inflammatory drugs (NSAIDs) and spontaneous abortionVersion 1.0, September 2016
Page 2 of 34
Copyright © Commonwealth of Australia 2016 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <[email protected]>.
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Contents Executive summary _____________________________ 4
2.2 Dosage forms ____________________________________________________________ 6
2.4 Scheduling status _______________________________________________________ 8
2.6 Regulatory and Pharmaceutical Benefit Scheme (PBS) funding status 8
2.7 Related products _______________________________________________________ 8
4 Product Information and labelling ______________ 9
4.1 Product Information ___________________________________________________ 9
5 Literature __________________________________ 15
5.2 Literature search _____________________________________________________ 19
5.2.1 Non-aspirin NSAIDs --------------------------------------------------------------- 19
5.2.2 Published guidelines ------------------------------------------------------------- 22
7 Discussion_________________________________ 27
TGA recommendations _______________________________________________________ 28
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Executive summary This issue arose from a pre-market review of the ‘Use in pregnancy’ section of the Product Information (PI) document for a naproxen-containing medicine. The review identified differences between the PIs of naproxen-containing medicines in regard to information about the potential risk of miscarriage after nonsteroidal anti-inflammatory drug (NSAID) exposure in early pregnancy. This observed discrepancy prompted an evaluation to determine whether this safety issue pertained to all NSAIDs, including aspirin.
The evaluation included comparisons of Australian and international product information documents across the range of NSAIDs; a review of mandated warnings, published literature and therapeutic guidelines; and an analysis of case reports from the TGA Adverse Drug Reactions System (ADRS) database.
NSAIDs are indicated for the treatment of pain, inflammation and fever. Aspirin is also indicated for the treatment of acute coronary syndrome and for the inhibition of platelet aggregation. NSAIDs are available in a variety of doses and formulations for a range of administration routes, including oral, rectal, parenteral, and topical. They are also available in combination products. Under the Poisons Standard February 2016, NSAIDs are classified as unscheduled or schedule 2, 3, or 4 medicines, depending on dose, dosage form and pack size.
A review of Australian and international NSAID product information documents demonstrated that the risk of spontaneous abortion is inconsistently included in Australian PIs across the different non-aspirin NSAIDs. At present, the Australian PIs for only five non-aspirin NSAIDs include a statement warning of the increased risk of miscarriage. The majority of non-aspirin NSAIDs which do not include a warning in their Australian PI have a statement in at least one international product reference document. Australian product information for aspirin alone is not available which is also the situation in the US and New Zealand. Neither the EU Summary of Product Characteristics (SmPC) nor the Canadian Product Monograph for aspirin documents an increased risk of spontaneous abortion.
NSAIDs that are not scheduled as an S4 are required to have various advisory statements on their medicine labels. The following advisory statement is used for NSAIDs in relation to the risk of use in pregnancy:
‘Do not use [this product/insert name of product] during the first 6 months of pregnancy, except on doctor’s advice. Do not use at all during the last 3 months of pregnancy.’
This advisory statement does not address the use in women who have just conceived and are therefore unlikely to be aware that they are pregnant. This is of relevance as the data to support the increased risk of miscarriage with non-aspirin NSAID use suggests that the risk is greatest when the non-aspirin NSAID is taken at the time of conception.
Diclofenac when indicated for children, non-aspirin NSAID preparations for dermal or external use and those which are indicated exclusively for dysmenorrhoea are not required to include this statement. The latter is of concern since treatment guidelines recommend pre-emptive treatment of dysmenorrhoea with non-aspirin NSAIDs and an implantation bleed can mimic the commencement of menstruation, with the potential for women who have conceived but are not yet aware, to self-treat for dysmenorrhoea. Additionally, given the increasing consumer awareness of over-the-counter (OTC) medicine marketing strategies, consumers may realise that NSAIDs indicated exclusively for dysmenorrhoea have the same active ingredient as NSAIDs not indicated exclusively for dysmenorrhoea despite the former being labelled specifically for “period pain”. Thus consumers may use non-aspirin NSAIDs that are indicated exclusively for dysmenorrhoea for other indications without being cautioned against the use whilst pregnant.
A review of the medical literature relating to NSAIDs and spontaneous abortion determined that on balance, the epidemiological data supports an association between non-aspirin NSAID use in
Therapeutic Goods Administration
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pregnancy and the risk of spontaneous abortion, particularly when the non-aspirin NSAID is taken close to the time of conception. The association between non-aspirin NSAID use and increased risk of miscarriage is widely accepted by professional medical organisations. Australian adverse event data was minimal for this association and provides limited support for a causal association. The association is biologically plausible and is supported by animal studies.
In regard to aspirin, there is at present insufficient evidence to support a causal association between aspirin use and an increased risk of miscarriage.
TGA recommendations 1. Harmonise the warnings in the product information for systemic and ophthalmic non-
aspirin NSAIDs in regard to the increased risk of spontaneous abortion when NSAIDs are taken around the time of conception.
2. Require all OTC non-aspirin NSAIDs, including those exclusively indicated for dysmenorrhoea, to include an advisory statement on their packaging which appropriately addresses the risk of spontaneous abortion.
3. Communicate the risk to health professionals and consumers.
Therapeutic Goods Administration
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1 Introduction This safety issue arose out of the evaluation of a pre-market application for a naproxen- containing combination product.1 The application proposed the inclusion of a statement in the ‘Use in Pregnancy’ section of the product information (PI) regarding a possible increased risk of miscarriage after the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in early pregnancy. The proposed wording was:
‘In humans, data from epidemiological studies suggest that there may be an increased risk of miscarriage after use of NSAIDs in early pregnancy.’
The application included clinical studies to support the inclusion of this statement. However, the innovator product for the non-aspirin NSAID did not include this information and the inconsistency prompted an investigation into whether this issue pertained to all NSAIDs and whether they required a similar warning in their PI.
2 Background
2.1 Mechanism of action NSAIDs work by inhibiting cyclo-oxygenase (COX) which in turn inhibits prostaglandin synthesis, giving this class of drugs its analgesic, antipyretic and anti-inflammatory properties. NSAIDs can be classified as nonselective (inhibiting both COX-1 and COX-2) or selective COX-2 inhibitors (celecoxib, etoricoxib, meloxicam, and parecoxib). Aspirin is included in the NSAID class of drugs despite having a slightly different mechanism of action to non-aspirin NSAIDs. Non-aspirin NSAIDs reversibly inhibit COX, whereas aspirin’s inhibition is irreversible.2
This review will examine the risk of spontaneous abortion with aspirin and non-aspirin NSAIDs separately.
2.2 Dosage forms There are 14 non-aspirin NSAID molecules on the ARTG that are registered for use in Australia. These are listed in the table below with information on available dosage forms and corresponding routes of administration.
Table 1: Dosage forms available in Australia for the investigated non-aspirin NSAIDs.
Active Ingredient Dosage form (route of administration)
Ibuprofen Tablet (oral), capsule (oral), liquid (oral), gel (topical), granules (oral)
Diclofenac Tablet (oral), capsule (oral), powder (oral), suppository (rectal), spray (topical), eye drops (ophthalmic), gel (topical)
Indometacin Capsule (oral), suppository (rectal), solution for aerosol pump (topical), powder for injection (intravenous)
Ketoprofen Suppository (rectal), capsule (oral)
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Ketorolac trometamol Tablet (oral), injection (intramuscular), eye drops (ophthalmic)
Mefenamic acid Capsule (oral)
Piroxicam Tablet (oral), capsule (oral), gel (topical)
Sulindac Tablet (oral)
Celecoxib Capsule (oral)
Etoricoxib Tablet (oral)
Parecoxib Powder for injection (intravenous, intramuscular)
Flurbiprofen Eye drops (ophthalmic), lozenges (oromucosal), granules (oral), solution for throat spray (oromucosal)
2.3 Indications for use Generally, non-aspirin NSAIDs are indicated for:2
· Pain due to inflammatory arthropathies, e.g. rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, gout, ankylosing spondylitis, psoriatic arthritis and Reiter’s syndrome
· Pain, especially due to inflammation and tissue injury (e.g. dysmenorrhoea, pericarditis, bone metastases, renal colic, headache, migraine, postoperative pain)
· Fever
Indometacin1 preparations that are intended for intravenous administration are exclusively indicated for the closure of patent ductus arteriosus in premature babies. Given the intended patient population, these products are not relevant to this review.
Aspirin irreversibly inhibits COX, reducing the synthesis of thromboxane A2 and thus inhibiting platelet aggregation for the life of the platelet.2 Additionally its effects and mechanisms of action vary with dose as follows:2
· Low doses: irreversibly acetylate serine 530 of COX-1 which inhibits platelet generation of thromboxane A12 (i.e. antithrombotic effect)
1 As of the 6th April 2016, the active ingredient indomethacin was renamed indometacin as part of the TGA’s update of medicine ingredient names intended to align Australian medicine names with those used internationally. This review will use the new name (indometacin) unless referring to a clinical study or official document which uses the old name (indomethacin).
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· High doses: mechanism of action includes both PG-dependant and independent effects (anti- inflammatory effects)
Aspirin is indicated for the following:2
· Inhibition of platelet aggregation
· Relief of pain, inflammation and fever
2.4 Scheduling status NSAIDs are available in a variety of doses and formulations for a range of administration routes, including oral, rectal, parenteral, and topical. Under the Poisons Standard February 2016, NSAIDs are classified as unscheduled or schedule 2, 3, or 4 medicines, depending on dose, dosage form and pack size.3
2.5 Specific conditions of use This safety issue pertains to females of childbearing age who are taking NSAIDs.
2.6 Regulatory and Pharmaceutical Benefit Scheme (PBS) funding status NSAIDs have been available for supply in Australia for many years. The first non-selective NSAIDs, which were developed in the 1960s and 1970s, were approved for marketing in Australia prior to the establishment of the ARTG in 1991. The selective COX-2 inhibitors have been approved for inclusion on the ARTG from 1999.
Data relating to PBS funding status and usage under the PBS scheme were not considered useful in the context of this evaluation as it would significantly underrepresent the usage of NSAIDs in Australia.
2.7 Related products There are a number of related products which contain a NSAID in combination with other medication/s including codeine, phenylephrine and pseudoephedrine. Aspirin is also available in combination with clopidogrel and dipyridamole.
3 The safety concern The safety concern is an increased risk of spontaneous abortion from taking NSAIDs during pregnancy.
The incidence of spontaneous abortion for clinically recognised pregnancies up to 20 weeks gestation is considered to be 8-20%. The incidence of subclinical pregnancy is higher, ranging from 22-26% as found in studies that assessed daily urinary human chorionic gonadotrophin levels.4
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It is recognised in the literature that there is a range of risk factors for spontaneous abortion, including the use of NSAIDs around the time of conception. Other risk factors include:5
· Advanced maternal age
– Prolonged time to conception
– Cocaine
– Caffeine
– Coeliac disease
The health risks associated with spontaneous abortion include the risk of endometritis, heavy bleeding and risks associated with a general anaesthetic and surgery if a dilatation and curettage is required. Additionally there is often a period of grieving for both the woman and partner after a miscarriage.6
4 Product Information and labelling
4.1 Product Information Australian and international PI documents (including the Food and Drug Administration label, Canadian Product Monograph, European Summary of Product Characteristics and New Zealand Data Sheet) for NSAIDs, were reviewed to determine whether the risk of spontaneous abortion is adequately documented.7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42, 43,44,45,46,47,
48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69
The review found that the risk of miscarriage is inconsistently included in Australian PI documents across the different non-Aspirin NSAIDs. At present, the Australian PIs for only five non-aspirin NSAIDs (ibuprofen, mefenamic acid, piroxicam, celecoxib and parecoxib) include a statement warning of the increased risk of miscarriage. The majority of non-aspirin NSAIDs which do not include a warning in their Australian PI have a statement in at least one international product reference document. In terms of the adequacy of the warnings, some PIs
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include a statement regarding increased pre-implantation and post-implantation losses in animal studies without a link to the clinical effect of an increased risk of spontaneous abortion. Australian product information for aspirin alone is not available. This situation is the same in the US and New Zealand. Neither the EU SmPC nor the Canadian Product Monograph for aspirin documents an increased risk of spontaneous abortion.70,71
Whilst many of the PIs do not specifically document the risk of spontaneous abortion they do note that the product should not be used in pregnancy unless the benefits outweigh the risks. All NSAIDs apart from celecoxib are classified under the ‘Australian categorisation system for prescribing medicines in pregnancy’ as category C2. Celecoxib is classed as category B33.
4.2 Required Advisory Statements for Medicine Labels (RASML) NSAIDs that are not scheduled as an S4 are required to have various advisory statements on their medicine labels as per the Medicines Advisory Statements Specification 2016. The following advisory statement is used for NSAIDs in relation to the risk in pregnancy. It states:72
‘Do not use [this product/insert name of product] during the first 6 months of pregnancy, except on doctor’s advice. Do not use at all during the last 3 months of pregnancy.’
RASML 2 came into effect on 1 January 2016 and has been consulted to identify the mandatory advisory statements for the different NSAIDs. Tables 2 and 3 summarise the requirements for non-aspirin NSAIDs and aspirin respectively in relation to the above advisory statement.72
Table 2: Required advisory statements relating to pregnancy for different non-aspirin NSAIDs and conditions
Non-aspirin NSAID
Conditions Statement Required?
Flurbiprofen In oral preparations that do NOT include indications for use in children under 12 years of age
Yes
In oral preparations that include indications for use in children under 12 years pf age
Yes
Ibuprofen In preparations for oral use when indicated exclusively for the treatment of dysmenorrhoea
No
2 Category C: Drugs which owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. 3 Category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
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Conditions Statement Required?
For the purpose of exclusion from the schedules to the SUSMP, when the preparation is for oral use and:
a. NOT indicated exclusively for the treatment of dysmenorrhoea; and
b. NOT indicated for use in children under 12 years of age
Yes
When included in a schedule to the SUSMP for oral use, and the preparation is:
a. NOT indicated exclusively for the treatment of dysmenorrhoea; and
b. NOT indicated for use in children under 12 years of age
Yes
For the purpose of exclusion from the schedules to the SUSMP, when the preparation is for oral use and:
a. the preparation includes indications for use in children under 12 years of age
Yes
When included in a schedule to the SUSMP for oral use, and:
a. the preparation includes indications for use in children under 12 years of age
Yes
In preparations for dermal use No
Diclofenac In preparations for oral use when indicated exclusively for the treatment of dysmenorrhoea
No
In preparations for oral use in adults and children aged 12 years and over, when NOT indicated exclusively for the treatment of dysmenorrhoea.
Yes
In preparations indicated for oral use in children under 12 years of age
No
Indomethacin In preparations for external use No
Ketoprofen In preparations for oral use indicated exclusively for the treatment of dysmenorrhoea
No
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a. NOT indicated exclusively for the treatment of dysmenorrhoea; and
b. NOT indicated for use in children under 12 years of age
Yes
When the preparation is for oral use and includes indications for use in children under 12 years of age
Yes
Mefenamic acid
No
Naproxen When indicated for oral use exclusively for the treatment of dysmenorrhoea
No
a. NOT indicated exclusively for the treatment of dysmenorrhoea; and
b. NOT indicated for use in children under 12 years of age
Yes
When the preparation includes indications of oral use in children under 12 years of age
Yes
The advisory statement states not to use the product in the first 6 months of pregnancy. The data to support the increased risk of miscarriage with non-aspirin NSAID use suggests that the risk is greatest when the non-aspirin NSAID is taken at the time of conception (discussed below). At this time, it is unlikely that a woman would be aware that she is pregnant. Ideally the warning should encompass women who are planning to become pregnant, such as advisory statement ‘Do not use if pregnant or likely to become pregnant’. Another option would be to alter the current statement to include those likely to be pregnant, for example, ‘Do not use [this product/insert name of product] if likely to become pregnant or during the first 6 months of pregnancy, except on doctor’s advice. Do not use at all during the last 3 months of pregnancy.’72
From the table above, diclofenac when indicated for children, non-aspirin NSAID preparations for dermal or external use and those which are indicated exclusively for dysmenorrhoea are not required to include this statement. Superficially the exclusion of this statement for products indicated exclusively for dysmenorrhoea seems reasonable as one would not expect a female who is pregnant to be self-treating for dysmenorrhoea. However, according to the Therapeutic Guidelines, NSAIDs are ideally taken 48 hours before menstruation is expected or with onset of pain.73 In these circumstances, it is possible that a woman planning to become pregnant, who has conceived but is not yet aware of the pregnancy, may pre-emptively take non-aspirin NSAIDs indicated exclusively for dysmenorrhoea and not be cautioned about the use during pregnancy. Alternatively, if a woman was not using these products pre-emptively, an implantation bleed
Therapeutic Goods Administration
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could mimic the early signs of menstruation, prompting a consumer to begin non-aspirin NSAID therapy for dysmenorrhoea relief whilst pregnant.
An additional impetus to include warnings on NSAIDs indicated exclusively for dysmenorrhoea relates to increasing consumer knowledge around the marketing strategies of OTC medicines. Consumers may realise that these NSAIDs have the same active ingredient as NSAIDs not indicated exclusively for dysmenorrhoea despite the former being labelled specifically for “period pain”. Thus consumers may use non-aspirin NSAIDS that are indicated exclusively for dysmenorrhoea for other indications without being cautioned against the…
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Copyright © Commonwealth of Australia 2016 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <[email protected]>.
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Contents Executive summary _____________________________ 4
2.2 Dosage forms ____________________________________________________________ 6
2.4 Scheduling status _______________________________________________________ 8
2.6 Regulatory and Pharmaceutical Benefit Scheme (PBS) funding status 8
2.7 Related products _______________________________________________________ 8
4 Product Information and labelling ______________ 9
4.1 Product Information ___________________________________________________ 9
5 Literature __________________________________ 15
5.2 Literature search _____________________________________________________ 19
5.2.1 Non-aspirin NSAIDs --------------------------------------------------------------- 19
5.2.2 Published guidelines ------------------------------------------------------------- 22
7 Discussion_________________________________ 27
TGA recommendations _______________________________________________________ 28
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Executive summary This issue arose from a pre-market review of the ‘Use in pregnancy’ section of the Product Information (PI) document for a naproxen-containing medicine. The review identified differences between the PIs of naproxen-containing medicines in regard to information about the potential risk of miscarriage after nonsteroidal anti-inflammatory drug (NSAID) exposure in early pregnancy. This observed discrepancy prompted an evaluation to determine whether this safety issue pertained to all NSAIDs, including aspirin.
The evaluation included comparisons of Australian and international product information documents across the range of NSAIDs; a review of mandated warnings, published literature and therapeutic guidelines; and an analysis of case reports from the TGA Adverse Drug Reactions System (ADRS) database.
NSAIDs are indicated for the treatment of pain, inflammation and fever. Aspirin is also indicated for the treatment of acute coronary syndrome and for the inhibition of platelet aggregation. NSAIDs are available in a variety of doses and formulations for a range of administration routes, including oral, rectal, parenteral, and topical. They are also available in combination products. Under the Poisons Standard February 2016, NSAIDs are classified as unscheduled or schedule 2, 3, or 4 medicines, depending on dose, dosage form and pack size.
A review of Australian and international NSAID product information documents demonstrated that the risk of spontaneous abortion is inconsistently included in Australian PIs across the different non-aspirin NSAIDs. At present, the Australian PIs for only five non-aspirin NSAIDs include a statement warning of the increased risk of miscarriage. The majority of non-aspirin NSAIDs which do not include a warning in their Australian PI have a statement in at least one international product reference document. Australian product information for aspirin alone is not available which is also the situation in the US and New Zealand. Neither the EU Summary of Product Characteristics (SmPC) nor the Canadian Product Monograph for aspirin documents an increased risk of spontaneous abortion.
NSAIDs that are not scheduled as an S4 are required to have various advisory statements on their medicine labels. The following advisory statement is used for NSAIDs in relation to the risk of use in pregnancy:
‘Do not use [this product/insert name of product] during the first 6 months of pregnancy, except on doctor’s advice. Do not use at all during the last 3 months of pregnancy.’
This advisory statement does not address the use in women who have just conceived and are therefore unlikely to be aware that they are pregnant. This is of relevance as the data to support the increased risk of miscarriage with non-aspirin NSAID use suggests that the risk is greatest when the non-aspirin NSAID is taken at the time of conception.
Diclofenac when indicated for children, non-aspirin NSAID preparations for dermal or external use and those which are indicated exclusively for dysmenorrhoea are not required to include this statement. The latter is of concern since treatment guidelines recommend pre-emptive treatment of dysmenorrhoea with non-aspirin NSAIDs and an implantation bleed can mimic the commencement of menstruation, with the potential for women who have conceived but are not yet aware, to self-treat for dysmenorrhoea. Additionally, given the increasing consumer awareness of over-the-counter (OTC) medicine marketing strategies, consumers may realise that NSAIDs indicated exclusively for dysmenorrhoea have the same active ingredient as NSAIDs not indicated exclusively for dysmenorrhoea despite the former being labelled specifically for “period pain”. Thus consumers may use non-aspirin NSAIDs that are indicated exclusively for dysmenorrhoea for other indications without being cautioned against the use whilst pregnant.
A review of the medical literature relating to NSAIDs and spontaneous abortion determined that on balance, the epidemiological data supports an association between non-aspirin NSAID use in
Therapeutic Goods Administration
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pregnancy and the risk of spontaneous abortion, particularly when the non-aspirin NSAID is taken close to the time of conception. The association between non-aspirin NSAID use and increased risk of miscarriage is widely accepted by professional medical organisations. Australian adverse event data was minimal for this association and provides limited support for a causal association. The association is biologically plausible and is supported by animal studies.
In regard to aspirin, there is at present insufficient evidence to support a causal association between aspirin use and an increased risk of miscarriage.
TGA recommendations 1. Harmonise the warnings in the product information for systemic and ophthalmic non-
aspirin NSAIDs in regard to the increased risk of spontaneous abortion when NSAIDs are taken around the time of conception.
2. Require all OTC non-aspirin NSAIDs, including those exclusively indicated for dysmenorrhoea, to include an advisory statement on their packaging which appropriately addresses the risk of spontaneous abortion.
3. Communicate the risk to health professionals and consumers.
Therapeutic Goods Administration
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1 Introduction This safety issue arose out of the evaluation of a pre-market application for a naproxen- containing combination product.1 The application proposed the inclusion of a statement in the ‘Use in Pregnancy’ section of the product information (PI) regarding a possible increased risk of miscarriage after the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in early pregnancy. The proposed wording was:
‘In humans, data from epidemiological studies suggest that there may be an increased risk of miscarriage after use of NSAIDs in early pregnancy.’
The application included clinical studies to support the inclusion of this statement. However, the innovator product for the non-aspirin NSAID did not include this information and the inconsistency prompted an investigation into whether this issue pertained to all NSAIDs and whether they required a similar warning in their PI.
2 Background
2.1 Mechanism of action NSAIDs work by inhibiting cyclo-oxygenase (COX) which in turn inhibits prostaglandin synthesis, giving this class of drugs its analgesic, antipyretic and anti-inflammatory properties. NSAIDs can be classified as nonselective (inhibiting both COX-1 and COX-2) or selective COX-2 inhibitors (celecoxib, etoricoxib, meloxicam, and parecoxib). Aspirin is included in the NSAID class of drugs despite having a slightly different mechanism of action to non-aspirin NSAIDs. Non-aspirin NSAIDs reversibly inhibit COX, whereas aspirin’s inhibition is irreversible.2
This review will examine the risk of spontaneous abortion with aspirin and non-aspirin NSAIDs separately.
2.2 Dosage forms There are 14 non-aspirin NSAID molecules on the ARTG that are registered for use in Australia. These are listed in the table below with information on available dosage forms and corresponding routes of administration.
Table 1: Dosage forms available in Australia for the investigated non-aspirin NSAIDs.
Active Ingredient Dosage form (route of administration)
Ibuprofen Tablet (oral), capsule (oral), liquid (oral), gel (topical), granules (oral)
Diclofenac Tablet (oral), capsule (oral), powder (oral), suppository (rectal), spray (topical), eye drops (ophthalmic), gel (topical)
Indometacin Capsule (oral), suppository (rectal), solution for aerosol pump (topical), powder for injection (intravenous)
Ketoprofen Suppository (rectal), capsule (oral)
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Ketorolac trometamol Tablet (oral), injection (intramuscular), eye drops (ophthalmic)
Mefenamic acid Capsule (oral)
Piroxicam Tablet (oral), capsule (oral), gel (topical)
Sulindac Tablet (oral)
Celecoxib Capsule (oral)
Etoricoxib Tablet (oral)
Parecoxib Powder for injection (intravenous, intramuscular)
Flurbiprofen Eye drops (ophthalmic), lozenges (oromucosal), granules (oral), solution for throat spray (oromucosal)
2.3 Indications for use Generally, non-aspirin NSAIDs are indicated for:2
· Pain due to inflammatory arthropathies, e.g. rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, gout, ankylosing spondylitis, psoriatic arthritis and Reiter’s syndrome
· Pain, especially due to inflammation and tissue injury (e.g. dysmenorrhoea, pericarditis, bone metastases, renal colic, headache, migraine, postoperative pain)
· Fever
Indometacin1 preparations that are intended for intravenous administration are exclusively indicated for the closure of patent ductus arteriosus in premature babies. Given the intended patient population, these products are not relevant to this review.
Aspirin irreversibly inhibits COX, reducing the synthesis of thromboxane A2 and thus inhibiting platelet aggregation for the life of the platelet.2 Additionally its effects and mechanisms of action vary with dose as follows:2
· Low doses: irreversibly acetylate serine 530 of COX-1 which inhibits platelet generation of thromboxane A12 (i.e. antithrombotic effect)
1 As of the 6th April 2016, the active ingredient indomethacin was renamed indometacin as part of the TGA’s update of medicine ingredient names intended to align Australian medicine names with those used internationally. This review will use the new name (indometacin) unless referring to a clinical study or official document which uses the old name (indomethacin).
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· High doses: mechanism of action includes both PG-dependant and independent effects (anti- inflammatory effects)
Aspirin is indicated for the following:2
· Inhibition of platelet aggregation
· Relief of pain, inflammation and fever
2.4 Scheduling status NSAIDs are available in a variety of doses and formulations for a range of administration routes, including oral, rectal, parenteral, and topical. Under the Poisons Standard February 2016, NSAIDs are classified as unscheduled or schedule 2, 3, or 4 medicines, depending on dose, dosage form and pack size.3
2.5 Specific conditions of use This safety issue pertains to females of childbearing age who are taking NSAIDs.
2.6 Regulatory and Pharmaceutical Benefit Scheme (PBS) funding status NSAIDs have been available for supply in Australia for many years. The first non-selective NSAIDs, which were developed in the 1960s and 1970s, were approved for marketing in Australia prior to the establishment of the ARTG in 1991. The selective COX-2 inhibitors have been approved for inclusion on the ARTG from 1999.
Data relating to PBS funding status and usage under the PBS scheme were not considered useful in the context of this evaluation as it would significantly underrepresent the usage of NSAIDs in Australia.
2.7 Related products There are a number of related products which contain a NSAID in combination with other medication/s including codeine, phenylephrine and pseudoephedrine. Aspirin is also available in combination with clopidogrel and dipyridamole.
3 The safety concern The safety concern is an increased risk of spontaneous abortion from taking NSAIDs during pregnancy.
The incidence of spontaneous abortion for clinically recognised pregnancies up to 20 weeks gestation is considered to be 8-20%. The incidence of subclinical pregnancy is higher, ranging from 22-26% as found in studies that assessed daily urinary human chorionic gonadotrophin levels.4
Therapeutic Goods Administration
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It is recognised in the literature that there is a range of risk factors for spontaneous abortion, including the use of NSAIDs around the time of conception. Other risk factors include:5
· Advanced maternal age
– Prolonged time to conception
– Cocaine
– Caffeine
– Coeliac disease
The health risks associated with spontaneous abortion include the risk of endometritis, heavy bleeding and risks associated with a general anaesthetic and surgery if a dilatation and curettage is required. Additionally there is often a period of grieving for both the woman and partner after a miscarriage.6
4 Product Information and labelling
4.1 Product Information Australian and international PI documents (including the Food and Drug Administration label, Canadian Product Monograph, European Summary of Product Characteristics and New Zealand Data Sheet) for NSAIDs, were reviewed to determine whether the risk of spontaneous abortion is adequately documented.7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42, 43,44,45,46,47,
48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69
The review found that the risk of miscarriage is inconsistently included in Australian PI documents across the different non-Aspirin NSAIDs. At present, the Australian PIs for only five non-aspirin NSAIDs (ibuprofen, mefenamic acid, piroxicam, celecoxib and parecoxib) include a statement warning of the increased risk of miscarriage. The majority of non-aspirin NSAIDs which do not include a warning in their Australian PI have a statement in at least one international product reference document. In terms of the adequacy of the warnings, some PIs
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include a statement regarding increased pre-implantation and post-implantation losses in animal studies without a link to the clinical effect of an increased risk of spontaneous abortion. Australian product information for aspirin alone is not available. This situation is the same in the US and New Zealand. Neither the EU SmPC nor the Canadian Product Monograph for aspirin documents an increased risk of spontaneous abortion.70,71
Whilst many of the PIs do not specifically document the risk of spontaneous abortion they do note that the product should not be used in pregnancy unless the benefits outweigh the risks. All NSAIDs apart from celecoxib are classified under the ‘Australian categorisation system for prescribing medicines in pregnancy’ as category C2. Celecoxib is classed as category B33.
4.2 Required Advisory Statements for Medicine Labels (RASML) NSAIDs that are not scheduled as an S4 are required to have various advisory statements on their medicine labels as per the Medicines Advisory Statements Specification 2016. The following advisory statement is used for NSAIDs in relation to the risk in pregnancy. It states:72
‘Do not use [this product/insert name of product] during the first 6 months of pregnancy, except on doctor’s advice. Do not use at all during the last 3 months of pregnancy.’
RASML 2 came into effect on 1 January 2016 and has been consulted to identify the mandatory advisory statements for the different NSAIDs. Tables 2 and 3 summarise the requirements for non-aspirin NSAIDs and aspirin respectively in relation to the above advisory statement.72
Table 2: Required advisory statements relating to pregnancy for different non-aspirin NSAIDs and conditions
Non-aspirin NSAID
Conditions Statement Required?
Flurbiprofen In oral preparations that do NOT include indications for use in children under 12 years of age
Yes
In oral preparations that include indications for use in children under 12 years pf age
Yes
Ibuprofen In preparations for oral use when indicated exclusively for the treatment of dysmenorrhoea
No
2 Category C: Drugs which owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible. 3 Category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
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Conditions Statement Required?
For the purpose of exclusion from the schedules to the SUSMP, when the preparation is for oral use and:
a. NOT indicated exclusively for the treatment of dysmenorrhoea; and
b. NOT indicated for use in children under 12 years of age
Yes
When included in a schedule to the SUSMP for oral use, and the preparation is:
a. NOT indicated exclusively for the treatment of dysmenorrhoea; and
b. NOT indicated for use in children under 12 years of age
Yes
For the purpose of exclusion from the schedules to the SUSMP, when the preparation is for oral use and:
a. the preparation includes indications for use in children under 12 years of age
Yes
When included in a schedule to the SUSMP for oral use, and:
a. the preparation includes indications for use in children under 12 years of age
Yes
In preparations for dermal use No
Diclofenac In preparations for oral use when indicated exclusively for the treatment of dysmenorrhoea
No
In preparations for oral use in adults and children aged 12 years and over, when NOT indicated exclusively for the treatment of dysmenorrhoea.
Yes
In preparations indicated for oral use in children under 12 years of age
No
Indomethacin In preparations for external use No
Ketoprofen In preparations for oral use indicated exclusively for the treatment of dysmenorrhoea
No
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a. NOT indicated exclusively for the treatment of dysmenorrhoea; and
b. NOT indicated for use in children under 12 years of age
Yes
When the preparation is for oral use and includes indications for use in children under 12 years of age
Yes
Mefenamic acid
No
Naproxen When indicated for oral use exclusively for the treatment of dysmenorrhoea
No
a. NOT indicated exclusively for the treatment of dysmenorrhoea; and
b. NOT indicated for use in children under 12 years of age
Yes
When the preparation includes indications of oral use in children under 12 years of age
Yes
The advisory statement states not to use the product in the first 6 months of pregnancy. The data to support the increased risk of miscarriage with non-aspirin NSAID use suggests that the risk is greatest when the non-aspirin NSAID is taken at the time of conception (discussed below). At this time, it is unlikely that a woman would be aware that she is pregnant. Ideally the warning should encompass women who are planning to become pregnant, such as advisory statement ‘Do not use if pregnant or likely to become pregnant’. Another option would be to alter the current statement to include those likely to be pregnant, for example, ‘Do not use [this product/insert name of product] if likely to become pregnant or during the first 6 months of pregnancy, except on doctor’s advice. Do not use at all during the last 3 months of pregnancy.’72
From the table above, diclofenac when indicated for children, non-aspirin NSAID preparations for dermal or external use and those which are indicated exclusively for dysmenorrhoea are not required to include this statement. Superficially the exclusion of this statement for products indicated exclusively for dysmenorrhoea seems reasonable as one would not expect a female who is pregnant to be self-treating for dysmenorrhoea. However, according to the Therapeutic Guidelines, NSAIDs are ideally taken 48 hours before menstruation is expected or with onset of pain.73 In these circumstances, it is possible that a woman planning to become pregnant, who has conceived but is not yet aware of the pregnancy, may pre-emptively take non-aspirin NSAIDs indicated exclusively for dysmenorrhoea and not be cautioned about the use during pregnancy. Alternatively, if a woman was not using these products pre-emptively, an implantation bleed
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could mimic the early signs of menstruation, prompting a consumer to begin non-aspirin NSAID therapy for dysmenorrhoea relief whilst pregnant.
An additional impetus to include warnings on NSAIDs indicated exclusively for dysmenorrhoea relates to increasing consumer knowledge around the marketing strategies of OTC medicines. Consumers may realise that these NSAIDs have the same active ingredient as NSAIDs not indicated exclusively for dysmenorrhoea despite the former being labelled specifically for “period pain”. Thus consumers may use non-aspirin NSAIDS that are indicated exclusively for dysmenorrhoea for other indications without being cautioned against the…
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